Direct-acting Antiviral Combination Research Articles

Hepatitis C virus-induced differential transcriptional traits in host cells after persistent infection elimination by direct-acting antivirals in cell culture.

Chronic hepatitis C virus infection (HCV) causes liver inflammation and fibrosis, leading to the development of severe liver disease, such as cirrhosis or hepatocellular carcinoma (HCC). Approval of direct-acting antiviral drug combinations has revolutionized chronic HCV therapy, with virus eradication in >98% of the treated patients. The efficacy of these treatments is such that it is formally possible for cured patients to carry formerly infected cells that display irreversible transcriptional alterations directly caused by chronic HCV Infection. Combining differential transcriptomes from two different persistent infection models, we observed a major reversion of infection-related transcripts after complete infection elimination. However, a small number of transcripts were abnormally expressed in formerly infected cells. Comparison of the results obtained in proliferating and growth-arrested cell culture models suggest that permanent transcriptional alterations may be established by several mechanisms. Interestingly, some of these alterations were also observed in the liver biopsies of virologically cured patients. Overall, our data suggest a direct and permanent impact of persistent HCV infection on the host cell transcriptome even after virus elimination, possibly contributing to the development of HCC.

Toward a Functional Cure for Hepatitis B.

Current treatment of chronic hepatitis B virus (HBV) infection, pegylated interferon-α (pegIFN-α) and nucleos(t)ide analogue (NA), can suppress HBV replication, reverse liver inflammation and fibrosis, and decrease risks of cirrhosis and hepatocellular carcinoma, but hepatitis B surface antigen (HBsAg) loss is rare. Functional HBV cure is defined as undetectable HBsAg and unquantifiable serum HBV DNA for at least 24 weeks after a finite course of therapy. This requires suppression of HBV replication and viral protein production as well as restoration of immune response to HBV. Direct-acting antivirals targeting virus entry, capsid assembly, viral protein production and secretion are in clinical trials. In parallel, immune modulatory therapies to stimulate HBV-specific immune response and to remove immune blockade are being tested. Clinical trials of direct-acting antivirals alone or immune modulatory therapies alone have not been successful in achieving HBV cure. Recent combinations of direct-acting antivirals and immune modulatory therapies have shown promising results particularly with combinations that included pegIFN-α. These results need to be confirmed in larger studies with longer follow-up, and further work is needed to develop simpler regimens with fewer drugs that can be administered orally and safely. While there is a strong desire to develop finite therapies that can achieve HBV cure, safety is paramount and new therapies must provide incremental value compared to standard of care, which is predominantly long-term NA therapy.

Hepatitis C: The Story of a Long Journey through First, Second, and Third Generation NS3/4A Peptidomimetic Inhibitors. What Did We Learn?

Hepatitis C viral (HCV) infection is the leading cause of liver failure and still represents a global health burden. Over the past decade, great advancements made HCV curable, and sustained viral remission significantly improved to more than 98%. Historical treatment with pegylated interferon alpha and ribavirin has been displaced by combinations of direct-acting antivirals. These regimens include drugs targeting different stages of the HCV life cycle. However, the emergence of viral resistance remains a big concern. The design of peptidomimetic inhibitors (PIs) able to fit and fill the conserved substrate envelope region within the active site helped avoid contact with the vulnerable sites of the most common resistance-associated substitutions Arg155, Ala156, and Asp168. Herein, we give an overview of HCV NS3 PIs discovered during the past decade, and we deeply discuss the rationale behind the structural optimization efforts essential to achieve pangenotypic activity.

CLINICAL PROFILE AND TREATMENT RESPONSE TO SOFOSBUVIR-VELPATASVIR REGIMEN AND ITS IMPACT ON THE QUALITY OF LIFE IN CHRONIC HEPATITIS C PATIENTS

Objective: Chronic Hepatitis C infection is one of the major global contributors to liver-related morbidity and mortality. Successful antiviral therapy with the direct-acting antiviral combination sofosbuvir-velpatasvir has shown to improve survival, liver-related outcomes, all-cause mortality, and even reverse fibrosis. We evaluated the treatment response of this regimen in terms of its impact on the Quality of life of patients during and after the therapy. Methods: This is an Observational, prospective, descriptive study of serologic HCV RNA-positive cases. Data on change in clinical, biochemical profile, and quality of life using 2 standardized questionnaires SF-36 and CLDQ was analyzed at baseline, 12 w from baseline, and 24 w after therapy cessation. Results: 62 out of the 87 patients registered during the study completed the desired study duration. 95% achieved sustained virological response (SVR) at 12 w and 100% at 24 w from baseline. Improved clinical profile with symptom resolution and change in the biochemical parameters and quality-of-life scores was statistically significant (P value-<0.001 and 0.005) at 12 w from baseline and 24 w after therapy cessation, respectively. Conclusion: Patients achieving SVR with sofosbuvir-velpatasvir have been shown to improve clinical profile with normalization in biochemical markers of liver disease, which is reflected in all the quality-of-life domains of SF-36 and CLDQ-HCV. However, long-term follow-up with larger sample size is required for improved study validity and to improve long-term liver-related outcomes.

Evolution of estimated glomerular filtration rate in HIV/HCV-coinfected patients who received direct-acting antivirals: A multicenter retrospective study.

The short-term impact of sofosbuvir (SOF)-based direct-acting antivirals (DAAs) combined with antiretroviral therapy (ART) on renal function in patients with HIV/HCV-coinfection remains controversial. This multicenter, retrospective study aimed to sequentially record the estimated glomerular filtration rate (eGFR) at baseline, end of therapy (EOT), 12 weeks off-treatment (SVR12), and at time points after SVR12 (post-SVR12) and to identify the factors associated with an eGFR decline to <60ml/min/1.73m2 in HIV/HCV-coinfected patients receiving DAAs. The evolution of mean eGFRs between different ART and DAAs combinations among patients of different HIV transmission routes were compared using a generalized linear mixed effects model. The periods between baseline and EOT, between EOT and post-SVR12, and between baseline and post-SVR12 were defined as the on-treatment, post-treatment, and all-course periods, respectively. Acute kidney disease (AKD) was defined as a decline of eGFR to <60ml/min/1.73m2. A total of 445 patients with baseline eGFRs >60ml/min/1.73m2 were included. We found that eGFRs declined during the on-treatment period in the tenofovir-containing ART and SOF-based DAA groups. There were no differences in the slope coefficient during the on-treatment and post-treatment periods among all risk groups except for people who inject drug. Increasing age and plasma HIV RNA >20 copies/ml before DAA treatment were factors independently associated with AKD during the on-treatment period while increasing age was independently associated with AKD during the all-course period. Only increasing age was an independent factor associated with AKD among HIV/HCV-coinfected patients during and after DAA treatments.

Elimination of hepatitis C virus in a prison: An 18-year experience

IntroductionDespite the decrease of hepatitis C in Spanish prisons in the last years, it still remains a reservoir for infection. The aim of this work is to analyze the characteristics of these patients and the response to antiviral treatment over the last 18 years. MethodsRetrospective observational study in inmates of Araba penitentiary center diagnosed with HCV infection between 2002 and 2020.A descriptive analysis of patient characteristics and the response to the three antiviral treatment modalities was performed: peg-interferon and ribavirin, peg-interferon, ribavirin and a first-generation protease inhibitor and different combinations of direct-acting antivirals. ResultsA total of 248 antiviral treatments were prescribed. Treatment response rate up to 2015 was 65% and 93,7% after that year. Interferon non-responders were the main cause of non-response to treatment in periods 1 and 2 (40%–50%). Conversely, in period 3 viral breakthrough (67%) was the main culprit. ConclusionAfter 18 years, active hepatitis C infection in prison inmates has resolved with treatment according to clinical criteria. Therefore, the stay in prison may represent an opportunity to reduce the reservoir of the disease in the community, together with continued health care for those released from prison.

Inhibition of Human Coronaviruses by Combinations of Host-Targeted and Direct-Acting Antivirals.

Antiviral compounds targeting cellular metabolism are part of the therapeutic arsenal to control the spread of virus infection, either as sole treatment or in combination with direct-acting antivirals (DAA) or vaccines. Here, we describe the effect of two of them, lauryl gallate (LG) and valproic acid (VPA) both exhibiting a wide antiviral spectrum, against infection by coronaviruses such as HCoV-229E, HCoV-OC43, and SARS-CoV-2. A consistent 2 to 4-log-decrease in virus yields was observed in the presence of each antiviral, with an average IC50 value of 1.6 μM for LG and 7.2 mM for VPA. Similar levels of inhibition were observed when adding the drug 1 h before adsorption, at the time of infection or 2 h after infection, supporting a postvirus entry mechanism of action. The specificity of the antiviral effect of LG against SARS-CoV-2, relative to other related compounds such as gallic acid (G) and epicatechin gallate (ECG), predicted to be better inhibitors according to in silico studies, was also demonstrated. The combined addition of LG, VPA, and remdesivir (RDV), a DAA with a proven effect against human coronaviruses, resulted in a robust synergistic effect between LG and VPA, and to a lesser extent between the other drug combinations. These findings reinforce the interest of these wide antiviral spectrum host-targeted compounds as a first line of defense against viral diseases or as a vaccine complement to minimize the gap in antibody-mediated protection evoked by vaccines, either in the case of SARS-CoV-2 or for other possible emerging viruses.

Eliminación del virus de la hepatitis C en un centro penitenciario: una experiencia de 18 años

IntroductionDespite the decrease of hepatitis C in Spanish prisons in the last years, it still remains a reservoir for infection. The aim of this work is to analyze the characteristics of these patients and the response to antiviral treatment over the last 18 years. MethodsRetrospective observational study in inmates of Araba penitentiary center diagnosed with HCV infection between 2002 and 2020.A descriptive analysis of patient characteristics and the response to the 3 antiviral treatment modalities was performed: peg-interferon and ribavirin, peg-interferon, ribavirin and a first-generation protease inhibitor and different combinations of direct-acting antivirals. ResultsA total of 248 antiviral treatments were prescribed. Treatment response rate up to 2015 was 65% and 93,7% after that year. Interferon non-responders were the main cause of non-response to treatment in periods 1 and 2 (40-50%). Conversely, in period 3 viral breakthrough (67%) was the main culprit. ConclusionAfter 18 years, active hepatitis C infection in prison inmates has resolved with treatment according to clinical criteria. Therefore, the stay in prison may represent an opportunity to reduce the reservoir of the disease in the community, together with continued health care for those released from prison.

Significance of pretreatment alpha-fetoprotein in patients with compensated severe fibrosis after hepatitis C viral eradication.

We aimed to investigate the factors associated with improvement of liver functional reserve after sustained virological response using interferon-free, direct-acting antiviral combination treatment in patients with compensated, severe fibrosis. Between September 2014 and April 2020, 492 patients received direct-acting antiviral combination treatment in our hospital. Among them, 173 patients who had severe fibrosis based on a fibrosis-4 index ≥3.25, showed sustained virological response after treatment. We investigated the dynamic change in albumin-bilirubin score and the baseline factors associated with its improvement, 48 weeks after treatment. The baseline significant factors associated with albumin-bilirubin≦ -0.5 were lower albumin (HR: 15.625, 95% CI: 4.273-58.824, P < .001), higher hepatitis C virus RNA (HR: 4.995, 95% CI: 1.882-13.260, P=.001), and higher alpha-fetoprotein (HR: 1.033, 95% CI: 1.011-1.055, P=.003). Patients with alpha-fetoprotein ≧10ng/mL showed significant improvement of albumin-bilirubin score from baseline to 48 weeks after treatment compared to those with alpha-fetoprotein <10ng/mL (P < .001). Baseline serum alpha-fetoprotein might be a predictive factor for improvement of liver function after sustained virological response in patients with severe fibrosis.

The efficacy of the direct-acting antiviral combination in hemodialysis patients with chronic hepatitis C virus Genotype 1 infection

Background Interferon and ribavirin treatments previously used in treating chronic hepatitis C virus (HCV) infection cannot be used effectively in hemodialysis patients due to dose adjustment and drug-related side effects. Direct-acting antivirals (DAAs) therapies have been reported to be effective in hemodialysis patients. This study aimed to evaluate the effectiveness of DAAs in hemodialysis patients with chronic hepatitis C.&#x0D; Material and Methods Twenty hemodialysis patients with chronic hepatitis C followed in the gastroenterology outpatient clinic between 2016 and 2018 were evaluated retrospectively.&#x0D; Results Twelve of the 20 patients were male, and eight were female. The mean age of the patients was 50.7±8.6 years. Six patients had no treatment experience. Fourteen patients had been previously treated with interferon and/or ribavirin but did not achieve sustained virological response (SVR). Genotype 1b was detected in 14 patients, genotype 1a in 4 patients, and genotype 1 in 2 patients. Patients were treated with ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) and dasabuvir (DSV) or ribavirin (RBV) for 12 or 24 weeks. Two patients were cirrhotic and had a Child-Pugh score of A. Treatment was discontinued in 2 patients due to thrombus formation in the arteriovenous fistula in the first month of DAAs treatment. SVR12 was evaluated in 14 of 18 patients and found to be 100%. One of the ten patients accepted as SVR24 had a relapse. This rate of SVR24 was similar to that in the general population.&#x0D; Conclusions Our results supported that the OBV/PTV/r and DSV or RBV regimen was a safe and effective therapy for hemodialysis patients with chronic hepatitis C virus genotype 1.

Sustained virological response (SVR) and safety of two direct acting anti-viral (DAA) combination therapies in Chronic Hepatitis-C infected patients of Lahore, Pakistan. A Randomized Controlled Trial

Chronic Hepatitis C (HCV) is a deadly infection affecting &gt; 185 million people worldwide and led to liver cirrhosis, hepatocellular carcinoma, or liver failure. Recently, treatment regimens of chronic HCV have entered the era of direct acting anti-virals (DAAs). Sustained virological response (SVR) rate is one of the best available tools to evaluate the efficacy of DAA treatments. Objective: To compare SVR rate and safety of two combinations of DAA treatments (Sofosbuvir and Daclatasvir vs Sofosbuvir and Velpatasvir) in chronic HCV infected patients of Lahore, Pakistan. Methods: Present randomized controlled trial was conducted at Mayo Hospital, Lahore, Pakistan and recruited 76 chronic HCV infected patients according to Consort guidelines. Registered patients were allocated in two groups by lottery method. Group A received sofobuvir with daclatasvir (SOFO + DCV) while group B received sofobuvir with velpatasvir (SOFO + VEL) treatment for 12 weeks. Response to therapy was evaluated in terms of SVR after 24 weeks and safety profile of the drug. Results: Both treatment groups showed high SVR 24 weeks after the completion of therapy. Group A (SOFO + DCV) presented 92% SVR while group B showed 97% SVR rate. Both DAA combination therapies presented good efficacy and safety profile. Few contraindications noted during the treatment included fatigue, arthritis, headache, loss of appetite and anemia. Conclusions: The efficacy of both DAA combination therapies was comparably high with &gt; 90% SVR rate. Group A proved safer as compared to group B. Studied DAA combinations are effective treatment options for chronic HCV treatment planning.

Evaluation of Drug Interactions in Patients Treated with DAAs for Hepatitis C Therapy with Comorbidities and Cardiovascular Issues—A Delphi Consensus Project

Orally administered direct-acting antivirals (DAAs) have dramatically changed the possibility of curing HCV (hepatitis C virus) infection, with the two principal HCV regimens based on the combination of glecaprevir + pibrentasvir (GLE-PIB) and sofosbuvir + velpatasvir (SOF-VEL). A combination of drugs containing NS3/4A protease inhibitors, as well as the fact that almost all HCV patients can be treated at present, may expose patients to a higher rate of drug-drug interactions (DDIs). The hepatitis C treatment recommendations from the EASL (European Association for the Study of the Liver) state that, prior to starting treatment with a DAA, a detailed drug history should be taken; yet, the decision on managing the potential DDIs is not always clear. For this reason, a group of Italian cardiologists and hepatologists promoted a survey among colleagues to assess the controversial issues when treating patients with chronic hepatitis C taking concomitant cardiovascular drugs, aiming to reach a consensus on the best practice to apply when treating a patient with chronic hepatitis C who is taking concomitant drugs for cardiovascular diseases. Two consecutive questionnaires were proposed between June and July 2022 to a qualitative Expert Panel (EP) of 14 gastroenterologists, infectologists, hepatologists, and internists, with statistical analyses performed on 100% of the responses for both questionnaires. Agreement among experts was assessed following the Delphi method as developed by the RAND Corporation. The interviewed experts consider DDIs a critical clinical problem to be evaluated in HCV patients. Therefore, dose changes, drug substitution, and discontinuation of concomitant cardiovascular drugs should be discouraged, even if planned for a relatively short period. Since oral DAAs have different DDIs profiles, hepatologists should prefer the antiviral DAA combination presenting the lowest instance of potential interactions.

Daclatasvir as a hepatitis C infection treatment option: an up-to-date evaluation

ABSTRACT Introduction Globally, it is estimated that 290,000 patients infected with hepatitis C virus (HCV) died from hepatitis C consequences, including cirrhosis and hepatocellular carcinoma in 2019. Although daclatasvir (DCV), combined with sofosbuvir (SOF), is effective in HCV patients, the new pan-genotypic combinations are considered by many as more cost-effective and successful in eradicating HCV infection. Areas covered This review discusses the safety, efficacy, and cost-effectiveness of DCV as an HCV treatment option based on real-world studies and pharmacoeconomic evaluations. Expert opinion Real-life studies suggest that SOF/DCV has acceptable sustained virological response and can be used successfully to manage HCV. Nonetheless, the use of SOF/DCV is limited by the longer treatment duration in genotype (GT)-3 patients and the need for ribavirin (RBV) in treatment-experienced patients which increases the likelihood of adverse effects. DCV is likely to remain as a therapeutic option for the management of GT-1, GT-2, and GT-4 patients in resource limited settings, while GT-3 patients are more likely to benefit from RBV-free direct-acting antiviral combinations such as SOF/velpatasvir for 12 weeks or glecaprevir/pibrentasvir for 8 weeks. The introduction of generics for these new pan-genotypic drugs would likely eliminate the need for SOF/DCV in the near future.

Precision Medicine: Determination of Ribavirin Urinary Metabolites in Relation to Drug Adverse Effects in HCV Patients.

The most commonly used antiviral treatment against hepatitis C virus is a combination of direct-acting antivirals (DAAs) and ribavirin (RBV), which leads to a shortened duration of therapy and a sustained virologic response until 98%. Nonetheless, several dose-related side effects of RBV could limit its applications. This study aims to measure the urinary concentration of RBV and its main metabolites in order to evaluate the drug metabolism ability of HCV patients and to evaluate the adverse effects, such as anemia, with respect to RBV metabolite levels. RBV and its proactive and inactive metabolites were identified and quantified in the urine of 17 HCV males with severe liver fibrosis using proton nuclear magnetic resonance (1H-NMR) at the fourth week (TW4) and at the twelfth week of treatment (EOT). Four prodrug urinary metabolites, including RBV, were identified and three of them were quantified. At both the TW4 and EOT stages, six HCV patients were found to maintain high concentrations of RBV, while another six patients maintained a high level of RBV proactive metabolites, likely due to nucleosidase activity. Furthermore, a negative correlation between the reduction in hemoglobin (Hb) and proactive forms was observed, according to RBV-triphosphate accumulation causing the hemolysis. These findings represent a proof of concept regarding tailoring the drug dose in relation to the specific metabolic ability of the individual, as expected by the precision medicine approach.

Use of contraindicated antiretroviral drugs in people with HIV/HCV coinfections receiving HCV treatment with direct-acting antivirals-Results from the EuroSIDA study.

Our objective was to determine whether antiretroviral drugs (ARVs) were used according to the European AIDS Clinical Society (EACS) guidelines for people with HIV/hepatitis C virus (HCV) coinfection treated with direct-acting antivirals (DAAs) between 30 November 2014 and 31 December 2019 in the pan-European EuroSIDA study. At each publication date of the EACS guidelines, plus 3 and 6 months, we calculated the number of people receiving DAAs with potential and actual ARV contraindications ('red shading' in the EACS guidelines). We used logistic regression to investigate factors associated with using contraindicated ARVs. Among 1406 people starting DAAs, the median age was 51 years, 75% were male, 57% reported injected drug use as an HIV risk, and 76% were from western Europe. Of 1624 treatment episodes, 609 (37.5%) occurred while the patient was receiving ARVs with potential contraindications; among them, 38 (6.2%; 95% confidence interval [CI] 4.3-8.2) involved a contraindicated ARV (18 non-nucleoside reverse transcriptase inhibitors), 16 involved protease inhibitors, and four involved integrase strand transfer inhibitors. The adjusted odds of receiving a contraindicated ARV were higher (3.25; 95% CI 1.40-7.57) among participants from east/central east Europe (vs. south) and lower (0.22; 95% CI 0.08-0.65) for 2015-2018 guidelines (vs. 2014). In total, 29 of the 32 (90.6%) patients receiving a contraindicated ARV and 441 of the 461 (95.7%) with potential ARV contraindications experienced a sustained virological response ≥12 weeks after stopping treatment (SVR12; p= 0.55). In this large heterogenous European cohort, more than one-third of people with HIV/HCV coinfection received DAAs with potential ARV contraindications, but few received a contraindicated ARV. Use of contraindicated ARVs declined over time, corresponding to the increased availability of ARV therapy regimens without interactions with DAA across Europe. Participants who received a contraindicated DAA and ARV combination still had a high rate of SVR12.

Efficacy and safety of sofosbuvir/velpatasvir with or without ribavirin in hepatitis C genotype 3 compensated cirrhosis: A meta-analysis

BACKGROUNDHepatitis C virus (HCV) is a leading cause of liver cirrhosis and hepatocellular carcinoma globally. Sofosbuvir/velpatasvir (SOF/VEL) is an effective pan-genotypic direct-acting antiviral combination for treatment of chronic HCV infection. While the addition of ribavirin (RBV) to SOF/VEL improved sustained virological response (SVR12) in genotype 3 (GT3) decompensated cirrhosis patients, the benefits of RBV in GT3 compensated cirrhosis patients receiving SOF/VEL remains unclear. AIMTo evaluate the efficacy and safety of SOF/VEL, with or without RBV in GT3 compensated cirrhosis patients. METHODSWe searched four electronic databases (PubMed/Medline, Embase, Cochrane Library and Web of Science) from inception up to June 2021 using both free text and MeSH terms. There was no restriction on language, geography, publication dates and publication status (full text or abstracts). All GT3 compensated cirrhosis patients treated with 12 wk of SOF/VEL, with or without RBV, were included, regardless of age, gender or prior treatment experience. The primary outcome was sustained virological response 12-wk post-treatment (SVR12). The secondary outcome was treatment-related adverse events, as defined by symptomatic anemia requiring transfusion or a drop in hemoglobin beyond 2 g/dL. The pooled relative risk (RR), 95%CI and heterogeneity (I2) were estimated using Review Manager version 5.3.RESULTSFrom 1752 citations, a total of seven studies (2 randomized controlled trials, 5 cohort studies) with 1088 subjects were identified. The SVR12 was similar in GT3 compensated cirrhosis patients, regardless of the use of RBV, for both the intention-to-treat RR 1.03, 95%CI: 0.99-1.07; I2 = 0%) and the per-protocol analysis (RR: 1.03, 95%CI: 0.99-1.07; I2 = 48%). The overall pooled rate of treatment-related adverse events was 7.2%. Addition of RBV increased the pooled risk of treatment-related adverse events in GT3 compensated cirrhosis patients receiving SOF/VEL (RR: 4.20, 95%CI: 1.29-13.68; I2 = 0%). Subgroup analysis showed that RBV was associated with a higher SVR12 in GT3 compensated cirrhosis patients with baseline resistance-associated substitutions. However, addition of RBV did not significantly increase the SVR12 among treatment-experienced GT3 compensated cirrhosis patients. CONCLUSIONRibavirin was not associated with higher SVR12 in GT3 compensated cirrhosis patients receiving SOF/VEL. Our findings suggest a limited role for RBV as routine add-on therapy to SOF/VEL in GT3 compensated cirrhosis patients.

Effectiveness of Ombitasvir with Paritaprevir/Ritonavir plus Ribavirin on the Treatment of Naïve Patients with Chronic Hepatitis C Virus Genotype 4

Background Direct-acting antivirals (DAAs) combination therapies from various mechanisms of action and families have been revolutionized the management landscape of chronic hepatitis C virus (HCV). Ombitasvir, paritaprevir with ritonavir (OBV/PTV/r) ± ribavirin (RBV) is approved to treat HCV genotype 4 (GT4) infection. Here, our objective was to delineate the efficacy and safety of OBV/PTV/r plus RBV in treating of Egyptian naïve patients infected with HCV GT4.&#x0D; Methods a cohort of 100 Egyptian patients infected with HCV GT4 was allocated and administered orally OBV/PTV/r with RBV. The primary endpoint of our study was a sustained virological response (HCV RNA &lt; 12 IU/mL) 12 weeks after the cessation of the treatment (SVR12). This study is registered with ClinicalTrials.gov, number NCT04378608.&#x0D; Results Among treatment naïve patients with OBV/PTV/r+ RBV, SVR12 rates achieved 97% (97/100) in overall patients. Regarding treatment failure, the regimen recorded 3 % had treatment failure (0 null-responses, 3 relapses). However, the most frequently common adverse events recorded were a headache (28%), fatigue (18%), asthenia (23%), nausea (19%) and dyspnea (14%).&#x0D; Conclusions The interferon-free regimen combination of OBV/PTV/r plus RBV achieved excellent SVR12 rates, 97%, with virologic outcome failures 3%, and it was generally safe and well tolerated for treating naïve patients infected with HCV GT4.

The Payer License Agreement, or "Netflix model," for hepatitis C virus therapies enables universal treatment access, lowers costs and incentivizes innovation and competition.

Background and AimsHigh unit prices of treatments limit access. For epidemics like that of hepatitis C virus (HCV), reduced treatment access increases prevalence and incidence, making the infectious disease increasingly difficult to manage. The objective of the current study was to construct and test an alternative pricing model, the Payer License Agreement (PLA), and determine whether it could improve outcomes, cut costs and incentivize innovation versus the current unit‐based pricing model.MethodsWe built and used computational models of hepatitis C disease progression, treatment, and pricing in historical and future scenarios and quantitatively analyzed their economic and epidemiological impact in three high‐income countries.ResultsThis study had three key results regarding HCV treatment. First, if the PLA model had been implemented when interferon‐free direct‐acting antiviral (DAA) combinations launched, the number of patients treated and cured would have more than doubled in the first three years, while the liver‐related deaths (LRDs) would have decreased by around 40%. Second, if the PLA model had been implemented beginning in 2018, the year that several Netflix‐like payment models were under implementation, the number of treated and cured patients would nearly double, and the LRDs would decline by more than 55%. Third, implementing the PLA model would result in a decline in total payer costs of more than 25%, with an increase to pharmaceutical manufacturer revenues of 10%. These results were true across the three healthcare landscapes studied, the USA, the UK and Italy, and were robust against variations to critical model parameters through sensitivity analysis.Conclusions and RelevanceThese results suggest that implementation of the PLA model in high‐income countries across a variety of health system contexts would improve patient outcomes at lower payer cost with more stable revenue for pharmaceutical manufacturers. Health policy‐makers in high‐income countries should consider the PLA model for application to more cost‐effective management of HCV, and explore its application for other infectious diseases with curative therapies available now or soon.

Road to elimination of HCV: Clinical challenges in HCV management.

Since its discovery in 1989, the road to a cure for hepatitis C virus (HCV) has been slow, but most patients can now expect to achieve a sustained virological response (SVR). With direct-acting antiviral (DAA) combination therapies such as glecaprevir/pibrentasvir and velpatasvir/sofosbuvir, 98% of patients successfully eradicate the virus, even if previous treatments failed or if resistance-associated substitutions (RASs) are present. Adverse events are rare or mild, and patients with compensated cirrhosis and other co-morbidities are often eligible for treatment. However, a small number of patients fail to eradicate the virus even after retreatment. The cause of failure is mainly due to emergence of NS5A P32 deletion mutants after initial DAA therapy in genotype 1b patients, although the reason is unknown for some patients. Alternative therapies that do not rely on NS5A inhibitors, such as sofosbuvir plus ribavirin, can be attempted in these patients. While scaled-up treatment efforts present a challenge, another problem is that many carriers are unaware of their infection. Long-term damage to the liver becomes irreversible, and patients who are not diagnosed in time can develop liver cancer or liver failure even after eliminating the virus. The long-term costs of treatment of advanced liver disease in undiagnosed patients relative to the immediate costs of DAA therapy should be considered. As no vaccine is yet available, eventual elimination of the virus requires identifying and treating undiagnosed cases and screening of high-risk populations such as injection drug users and men who have sex with men and female sex workers.

Efficacy and Safety of Glecaprevir/Pibrentasvir in Korean Patients with Chronic Hepatitis C: A Pooled Analysis of Five Phase II/III Trials.

Background/AimsGlecaprevir/pibrentasvir (G/P) is the first pan-genotypic direct-acting antiviral combination therapy approved in Korea. An integrated analysis of five phase II and III trials was conducted to evaluate the efficacy and safety of G/P in Korean patients with chronic hepatitis C virus (HCV) infection.MethodsThe study analyzed pooled data on Korean patients with HCV infection enrolled in the ENDURANCE 1 and 2, SURVEYOR II part 4 and VOYAGE I and II trials, which evaluated the efficacy and safety of 8 or 12 weeks of G/P treatment. The patients were either treatment-naïve or had received sofosbuvir or interferon-based treatment. Efficacy was evaluated by assessing the rate of sustained virologic response at 12 weeks posttreatment (SVR12). Safety was evaluated by monitoring adverse events (AEs) and laboratory assessments.ResultsThe analysis included 265 patients; 179 (67.5%) were HCV treatment-naïve, and most patients were either subgenotype 1B (48.7%) or 2A (44.5%). In the intention-to-treat population, 262 patients (98.9%) achieved SVR12. Three patients did not achieve SVR12 one had virologic failure and two had non-virologic failures. Most AEs were grade 1/2; eight patients (3.0%) experienced at least one grade ≥3 AE. No serious AEs related to G/P treatment were reported, and grade ≥3 hepatic laboratory abnormalities were rare (0.8%).ConclusionsG/P therapy was highly efficacious and well tolerated in Korean patients with HCV infection, with most patients achieving SVR12. The safety profile was comparable to that observed in a pooled analysis of a global pan-genotypic population of patients with HCV infection who received G/P.